The overall goal of the FRIENDS Children's Environmental Health Center is to understand the impact of[unreadable] prenatal exposure to contaminants found in fish-including polychlorinated biphenyls (PCBs),[unreadable] polybrominated diphenyl ethers (PBDEs) and methyl mercury (MeHg)-on cognitive, motor and auditory[unreadable] function of children. The animal studies described in this proposal will complement a parallel prospective[unreadable] birth cohort study (Project 2) in which children born to women consuming fish contaminated with these[unreadable] chemicals will be followed longitudinally from birth. The animal studies will'use an experimental PCB mixture[unreadable] that mimics the PCB congener profile in the fish consumed by women in the epidemiological study. One[unreadable] major goal is to elucidate the effects of PCBs and PBDEs on important executive processes including[unreadable] attention and inhibitory control. Drug challenges with methylphenidate and amphetamine will determine if[unreadable] commonly prescribed ADHD pharmacotherapies improve the performance of PCB- or PBDE-exposed rats[unreadable] on tests of attention and response inhibition, and measures of DA D4 and DA D1 receptor expresion and[unreadable] drug challenges using specific DA D4 and DA D1 receptor agonists will indicate whether these receptor[unreadable] pathways are involved in mediating the behavioral effects. These studies will be conducted in parallel with[unreadable] another laboratory study (Project 4) which will investigate the effects of PCB and PBDE exposure on central[unreadable] catecholamine function and the extent to which these effects are mediated indirectly through PCB or PBDE[unreadable] effects on circulating thyroid hormones. A second major goal is to understand the mechanisms through[unreadable] which PCBs damage the cohclea and produce hearing loss. Histological examinations of the cochlea will[unreadable] confirm whether hearing deficits are due to outer hair cell damage. The contribution of reductions in[unreadable] circulating thyroid hormones or alterations in ryanodine receptor expression in the cochlea to PCB-induced[unreadable] hearing loss will be investigated by utilizing two specific PCB congeners having opposing effects on thyroid[unreadable] hormones and ryanodine channel activity. Because the outer hair cells are believed to protect against noise[unreadable] induced hearing loss, studies will also be conducted to determine if early PCB exposure increases[unreadable] susceptibility to noise-induced hearing loss later in life. As in the past, findings from these animal studies will[unreadable] guide the selection of outcome measures for use in the birth cohort.